WO2011155689A2 - Procédé de préparation d'un intermédiaire de pitavastatine ou de son sel - Google Patents

Procédé de préparation d'un intermédiaire de pitavastatine ou de son sel Download PDF

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Publication number
WO2011155689A2
WO2011155689A2 PCT/KR2011/001704 KR2011001704W WO2011155689A2 WO 2011155689 A2 WO2011155689 A2 WO 2011155689A2 KR 2011001704 W KR2011001704 W KR 2011001704W WO 2011155689 A2 WO2011155689 A2 WO 2011155689A2
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WIPO (PCT)
Prior art keywords
formula
compound
dimethyl sulfoxide
solvate
pitavastatin
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PCT/KR2011/001704
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English (en)
Korean (ko)
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WO2011155689A3 (fr
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이서진
김현규
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H L GENOMICS
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H L GENOMICS
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Priority to CN201180028329.3A priority Critical patent/CN102971297B/zh
Priority to US13/701,723 priority patent/US20130072688A1/en
Priority to JP2013514094A priority patent/JP5796836B2/ja
Publication of WO2011155689A2 publication Critical patent/WO2011155689A2/fr
Publication of WO2011155689A3 publication Critical patent/WO2011155689A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to an improved process for the preparation of intermediates of pitavastatin or salts thereof, and more particularly to (4R, 6S)-(E) -6- [2- (2-cyclo which is an intermediate of pitavastatin or salts thereof.
  • (4R, 6S)-(E) -6- [2- (2-cyclo which is an intermediate of pitavastatin or salts thereof.
  • the present invention also relates to novel solvates of the intermediates and methods of preparing pitavastatin or salts thereof using the intermediates.
  • Phytavastatin or salts thereof are useful as therapeutic agents for hypercholesterolemia by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase and inhibiting cholesterol biosynthesis in the human body do.
  • Salts of pitavastatin are known in the form of sodium salts, potassium salts, hemicalcium salts, magnesium salts, etc., and are used in the clinic in the form of hemicalcium salts.
  • the chemical structure of pitavastatin or a salt thereof is as shown in the following formula, in which M represents hydrogen, Na + , K + , Mg +2 , Ca +2 and the like.
  • WO2007 / 132482 discloses a process for preparing pitavastatin or a salt thereof under mild conditions through a relatively short reaction step.
  • the patent discloses a compound of formula 2 and tert-butyl-2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl, as shown in Scheme 1 below.
  • Acetate is reacted via a Wittig reaction to produce an intermediate having a dioxane moiety, which is then converted to the amine salt form of the intermediate having a dihydroxy moiety, followed by the preparation of pitavastatin or a salt thereof. .
  • the intermediate having a dioxane moiety is separated by a separation process such as extraction, concentration using toluene.
  • a separation process such as extraction, concentration using toluene.
  • the intermediate is obtained in the form of an oil (that is, in the form of a concentrated residue), which is difficult to handle.
  • the purity of the intermediate with the resulting dioxane moiety is very low (about 75% purity when analyzed by HPLC, see FIG. 1), and the triphenyl phosphine oxide resulting from the witting reaction is also about 2% of the intermediate. Remaining.
  • the preparation method performs a purification step of converting an intermediate having a reaction product, that is, a dihydroxy moiety, into an amine salt form.
  • the conversion process to the amine salt form has to be carried out additionally, the process is not only long, the yield is reduced in the process, and also the purity of pitavastatin and its salts obtained from the amine salt form is up to HPLC 95 Only%, purity is still not satisfactory.
  • the present invention provides an improved process by which intermediates with dioxane moieties can be prepared in solid crystalline form in a simple manner, without cumbersome post-treatment processes such as organic solvent extraction.
  • an improved method for producing such intermediates with high purity of 99% or higher.
  • the present invention provides a method capable of producing pitavastatin or a salt thereof in high purity using the improved method.
  • the present invention provides an improved process for preparing intermediates in solid crystalline form useful for the preparation of pitavastatin or salts thereof.
  • the present invention also provides a novel solvate of the intermediate in the above solid crystalline form and a process for preparing the same.
  • the present invention also provides a method for preparing pitavastatin or a salt thereof using the intermediate in the solid crystalline form or solvate thereof.
  • step (a) conducting a reaction of a compound of formula 2 with a compound of formula 3 in the presence of a base; And (b) adding C 1 -C 4 alcohol to the reaction mixture of step (a) to form a precipitate, and then washing the obtained precipitate with water and drying to obtain a compound of formula (4).
  • Processes for the preparation of compounds of formula 4 are provided:
  • R is a carboxylic acid protecting group.
  • the base may be an alkali metal salt
  • the C 1 to C 4 alcohol may be selected from one or more selected from the group consisting of methanol, ethanol, and 2-propanol.
  • the step of forming the precipitate may be carried out by adding the C 1 ⁇ C 4 alcohol at 40 to 45 °C reaction mixture of the compound of Formula 2 and the compound of Formula 3, and then cooled to 5 to 15 °C .
  • step (c) reacting a compound of formula 2 with a compound of formula 3 in the presence of a base using dimethyl sulfoxide in a ratio of 3 to 7 L relative to 1 kg of compound of formula 2 is used as a reaction solvent. Performing; And (d) cooling the reaction mixture of step (c) to 20-25 ° C. to form a precipitate, and then washing the obtained precipitate with a mixed solvent of dimethyl sulfoxide and hexane and drying to form a dimethyl sulfoxide-solvate.
  • the base may be an alkali metal salt.
  • R is a carboxylic acid protecting group.
  • the preparation method according to the present invention can obtain an intermediate (ie, a compound of formula 4) or its dimethylsulfoxide-solvate in solid crystalline form, thus avoiding the difficulty in handling the oily intermediate compound.
  • the intermediate of the solid crystalline form or dimethyl sulfoxide-solvate thereof is obtained with high purity of 99% or more, so that the compound of formula 5 having a dihydroxy moiety can be prepared in high purity.
  • phytavastatin or salts thereof can be prepared directly from the compound of formula 5, without the need to perform the process of converting the compound of formula 5 to the amine salt form, thus reducing the reaction process to a large industrial scale.
  • Figure 1 shows the results of HPLC analysis of the product prepared by the preparation method according to Example 3 of WO2007 / 132482. Arrows in FIG. 1 are peaks of intermediates with dioxane moieties.
  • FIG. The arrow in FIG. 2 is the peak of the product.
  • the present invention comprises the steps of (a) conducting a reaction of a compound of Formula 2 with a compound of Formula 3 in the presence of a base; And (b) adding C 1 -C 4 alcohol to the reaction mixture of step (a) to form a precipitate, and then washing the obtained precipitate with water and drying to obtain a compound of formula (4).
  • R is a carboxylic acid protecting group.
  • the carboxylic acid protecting group is C 1 -C 5 straight or branched alkyl or benzyl; Preferably tert-butyl.
  • the preparation method according to the present invention can obtain the compound of formula 4 as a solid crystalline form, it is possible to avoid the difficulty in handling the oily intermediate compound (ie, the compound of formula 4).
  • the compound of formula 4 in the solid crystalline form is obtained with a high purity of 99% or more, so that the compound of formula 5 having a dihydroxy moiety can be prepared in high purity.
  • the reaction process can be shortened, which is suitable for mass production on an industrial scale.
  • unlike the conventional manufacturing method by crystallization using a low-cost alcohol solvent without the separation process such as extraction, concentration using toluene, it is possible to simplify the manufacturing process and lower the manufacturing cost.
  • step (a) can be carried out according to a conventional manufacturing method (ie, International Patent Publication WO 2007/132482). That is, the compound of formula 2 obtained from the reaction with 3- (bromomethyl) -2- (1-cyclopropyl) -4- (4'-fluorophenyl) quinoline and triphenyl phosphine is prepared in the presence of a base It can be carried out by reacting with a compound of.
  • the base may be an alkali metal salt, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like, preferably potassium carbonate.
  • step (a) may be carried out at a temperature of 50 to 90 ° C, preferably about 70 ° C.
  • organic solvents such as dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and the like may be used.
  • the C 1 to C 4 alcohol of step (b) may be selected from one or more selected from the group consisting of methanol, ethanol, and 2-propanol, preferably methanol or ethanol.
  • a precipitate is formed, and the precipitate can be separated by filtration according to a conventional method.
  • triphenyl phosphine oxide produced as a by-product is simply removed, whereby the compound of formula 4 in solid crystalline form can be separated with high purity.
  • the process of forming the precipitate may be carried out by adding the C 1 -C 4 alcohol at 40 to 45 °C the reaction mixture of step (a), and then cooled to 5 to 15 °C.
  • the used base is removed by the water washing process of step (b).
  • the water washing process may be performed by a conventional washing method, for example, it may be performed using water in a ratio of 5 to 30 L per 1 kg of precipitate obtained in the previous process, and the washing process may be performed at least once. It may be.
  • the product obtained after washing with water can be separated by drying according to a conventional drying method, for example, vacuum drying.
  • the present invention also provides a process for the preparation of dimethyl sulfoxide-solvate of a compound of formula 4 in solid crystalline form. That is, the present invention (c) using a dimethyl sulfoxide in a ratio of 3 to 7 L relative to 1 kg of the compound of formula 2 as a reaction solvent, the reaction of the compound of formula 2 and the compound of formula 3 in the presence of a base ; And (d) cooling the reaction mixture of step (c) to 20-25 ° C. to form a precipitate, and then washing the obtained precipitate with a mixed solvent of dimethyl sulfoxide and hexane and drying to form a dimethyl sulfoxide-solvate.
  • a process for the preparation of a dimethyl sulfoxide-solvate of a compound of formula 4 in solid crystalline form comprising the step of obtaining a compound of formula 4.
  • the method for preparing dimethylsulfoxide-solvate of the compound of formula 4 according to the present invention can obtain the compound of formula 4 as a solid crystalline form, thereby avoiding the difficulty in handling the oily intermediate compound (ie, the compound of formula 4) can do.
  • the compound of formula 4 in the solid crystalline form is obtained with a high purity of 99% or more, so that the compound of formula 5 having a dihydroxy moiety can be prepared in high purity.
  • there is no need to carry out the process of converting the compound of formula 5 to the amine salt form as in conventional methods of preparation (ie WO 2007/132482), phytavastatin or Since salts can be prepared, the reaction process can be shortened, which is suitable for mass production on an industrial scale.
  • step (c) is a conventional method of manufacturing (ie, international patent publication WO 2007/132482), except that a small amount of dimethyl sulfoxide, a reaction solvent, is used in a ratio of 3 to 7 L based on 1 kg of the compound of the formula (2). May be performed according to
  • the base used may be an alkali metal salt, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like, preferably potassium carbonate.
  • the process of step (c) may be carried out at a temperature of 50 to 90 °C.
  • step (c) Cooling the reaction mixture of step (c) to 20-25 ° C. forms a precipitate, which can be separated by filtration in accordance with conventional methods.
  • the precipitate obtained was washed with a mixed solvent of dimethyl sulfoxide and hexane, thereby removing triphenyl phosphine oxide and the like produced from the base and by-products used to remove dimethyl sulfoxide-solvate of the compound of formula 4 in solid crystalline form with high purity.
  • the weight ratio of dimethyl sulfoxide and hexane in the mixed solvent of dimethyl sulfoxide and hexane may be, for example, in the range of 1: 0.5 to 5, but is not limited thereto.
  • the obtained product, ie, the dimethylsulfoxide-solvate of the compound of formula 4 can be separated by drying according to a conventional drying method, for example, a reduced pressure drying method.
  • the dimethylsulfoxide-solvate of the compound of formula 4 in solid crystalline form is a novel compound, useful as an intermediate for the preparation of pitavastatin or a pharmaceutically acceptable salt thereof. Accordingly, the present invention includes the dimethylsulfoxide-solvate of the compound of formula 4:
  • R is a carboxylic acid protecting group.
  • the carboxylic acid protecting group is C 1 -C 5 straight or branched alkyl or benzyl; Preferably tert-butyl.
  • the compound of formula 4 or dimethyl sulfoxide-solvate thereof in the form of a solid crystalline form obtained according to the present invention is used directly in the subsequent reaction without undergoing a separate purification process or an amine salt conversion process, so that pitavastatin or pharmaceutical Alternatively, acceptable salts can be prepared with high purity of at least 99%.
  • the present invention comprises the steps of (e) preparing a compound of formula (4) or dimethyl sulfoxide-solvate thereof in solid crystalline form by the above method; (f) adding an acid to the compound of formula 4 or its dimethylsulfoxide-solvate in solid crystalline form to convert the compound to formula 5; (g) adding sodium hydroxide to the compound of Formula 5 to convert it into a pitavastatin free base (compound of Formula 1); And (h) optionally converting said pitavastatin free base into a pharmaceutically acceptable salt.
  • R is a carboxylic acid protecting group.
  • step (f) may be carried out by adding an acid to the compound of formula 4 or its dimethylsulfoxide-solvate in solid crystalline form prepared by the preparation method as described above, and converting it to the compound of formula 5.
  • the acid treatment converts the dioxane moiety to a dihydroxy moiety.
  • the acid for example, hydrochloric acid, acetic acid, sulfuric acid, etc. may be used, and hydrochloric acid may be preferably used.
  • the amount of the acid may be in the range of 1 to 5 equivalents, preferably 2 to 3 equivalents based on 1 equivalent of the compound of formula 4 or dimethyl sulfoxide-solvate thereof, but is not limited thereto.
  • the reaction may be carried out in a solvent such as acetonitrile, methanol, ethanol for 2-3 hours.
  • the reaction product can be separated by a process such as neutralization, crystallization using ethyl acetate and hexane, filtration, and drying.
  • step (g) is converted to pitavastatin free base by adding sodium hydroxide to the compound of formula 5 to remove the protecting group.
  • the amount of the sodium hydroxide may be in the range of 1 to 5 equivalents based on 1 equivalent of the compound of Formula 5, but is not limited thereto.
  • step (h) is a step of converting the pitavastatin free base into a pharmaceutically acceptable salt, which is a conventional method (for example, Korean Patent Registration No. 10-0208867).
  • a pharmaceutically acceptable salt for example, Korean Patent Registration No. 10-0208867.
  • Pharmaceutically acceptable salts of pitavastatin include conventional pitavastatin salts such as sodium salts, potassium salts, hemicalcium salts, magnesium salts, and are preferably hemicalcium salts.
  • conversion to hemicalcium salts can be carried out by reacting calcium halides such as calcium chloride.

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  • Organic Chemistry (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Quinoline Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un dérivé ester de l'acide (4R,6S)-(E)-6-[2-(2-cyclopropyl)-4-(4-fluorophényl)quinoléin-3- yl]vinyl-2,2-diméthyl-1,3-dioxane-4-yl]acétique, un intermédiaire de la pitavastatine, ou de son sel sous une forme cristalline solide. L'invention concerne en outre un nouveau solvate de l'intermédiaire, ainsi qu'un procédé de préparation de pitavastatine ou de son sel en utilisant ledit intermédiaire.
PCT/KR2011/001704 2010-06-08 2011-03-11 Procédé de préparation d'un intermédiaire de pitavastatine ou de son sel Ceased WO2011155689A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201180028329.3A CN102971297B (zh) 2010-06-08 2011-03-11 匹伐他汀或其盐的中间体的制备方法
US13/701,723 US20130072688A1 (en) 2010-06-08 2011-03-11 Method for preparing an intermediate of pitavastatin or of the salt thereof
JP2013514094A JP5796836B2 (ja) 2010-06-08 2011-03-11 ピタバスタチンまたはその塩の中間体の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2010-0053631 2010-06-08
KR1020100053631A KR100995882B1 (ko) 2010-06-08 2010-06-08 피타바스타틴 또는 그의 염의 중간체의 제조방법

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WO2011155689A2 true WO2011155689A2 (fr) 2011-12-15
WO2011155689A3 WO2011155689A3 (fr) 2012-02-02

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US (1) US20130072688A1 (fr)
JP (1) JP5796836B2 (fr)
KR (1) KR100995882B1 (fr)
CN (2) CN103833737A (fr)
WO (1) WO2011155689A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015513556A (ja) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． 新規なスタチン中間体、並びにこれを用いたピタバスタチン、ロスバスタチン、セリバスタチン及びフルバスタチンの製造方法

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CN108976168B (zh) * 2017-06-02 2020-09-25 浙江京新药业股份有限公司 一种匹伐他汀半钙盐晶型及其制备方法
CN117050012A (zh) * 2023-06-27 2023-11-14 江苏天晟药业股份有限公司 一种3，5-二羟基-6-庚烯酸钠的制备方法

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JP2569746B2 (ja) * 1987-08-20 1997-01-08 日産化学工業株式会社 キノリン系メバロノラクトン類
JPH05310700A (ja) * 1992-05-12 1993-11-22 Sagami Chem Res Center 縮合ピリジン系メバロノラクトン中間体及びその製法
JP4213390B2 (ja) * 2001-02-02 2009-01-21 武田薬品工業株式会社 縮合複素環化合物
EP1466905B1 (fr) * 2001-11-14 2011-05-18 Nissan Chemical Industries, Ltd. Production d'ester d'acide oxoheptonoique optiquement actif
JP2004099540A (ja) * 2002-09-10 2004-04-02 Nippon Kasei Chem Co Ltd ヘキサヒドロ−３ｈ−ナフタレン−２−オン誘導体およびその製造方法ならびにヘキサヒドロ−３ｈ−ナフタレン−２−オン誘導体のエナミン
CA2510625A1 (fr) * 2002-12-12 2004-07-01 Teva Pharmaceutical Industries Ltd. Formes cristallines de gatifloxacine et procedes de preparation associes
WO2007132482A2 (fr) * 2006-05-17 2007-11-22 Manne Satyanarayana Reddy Nouveau procédé de synthèse de pitavastatine et de ses sels de qualité pharmaceutique
JP2010530367A (ja) * 2007-06-15 2010-09-09 ソルベイ・フアーマシユーチカルズ・ベー・ブイ カンナビノイドｃｂ１受容体モジュレーターとしての４，５−ジヒドロ−（１ｈ）−ピラゾール誘導体
KR101063146B1 (ko) * 2008-11-10 2011-09-07 미래파인켐 주식회사 피타바스타틴 중간체의 제조방법 및 이를 이용한 피타바스타틴 헤미 칼슘염의 제조방법
US8487105B2 (en) * 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015513556A (ja) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． 新規なスタチン中間体、並びにこれを用いたピタバスタチン、ロスバスタチン、セリバスタチン及びフルバスタチンの製造方法

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JP2013529223A (ja) 2013-07-18
CN102971297A (zh) 2013-03-13
KR100995882B1 (ko) 2010-11-22
CN103833737A (zh) 2014-06-04
WO2011155689A3 (fr) 2012-02-02
CN102971297B (zh) 2014-12-10
US20130072688A1 (en) 2013-03-21
JP5796836B2 (ja) 2015-10-21

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